Q9Y5C1 · ANGL3_HUMAN
- ProteinAngiopoietin-related protein 3
- GeneANGPTL3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids460 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645).
Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity).
Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395).
Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676).
Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906).
Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity).
Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).
Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity).
Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395).
Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676).
Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906).
Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity).
Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).
ANGPTL3(17-221)
In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL.
Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390).
Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744).
May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity).
Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744).
May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity).
Miscellaneous
Was suggested to inhibit LPL through a direct mechanism; however, the necessary concentration to achieve in vitro inhibition is at least 30-fold higher than ANGPTL3 plasma concentration.
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameAngiopoietin-related protein 3
- Alternative names
- Cleaved into 2 chains
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9Y5C1
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Colocalized with HSPG2 and activated ITGB3 on podocytes.
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Hypobetalipoproteinemia, familial, 2 (FHBL2)
- Note
- DescriptionA disorder of lipid metabolism characterized by less than 5th percentile age- and sex-specific levels of low density lipoproteins, and dietary fat malabsorption. Affected individuals present with combined hypolipidemia, consisting of extremely low plasma levels of LDL cholesterol, HDL cholesterol, and triglycerides.
- See alsoMIM:605019
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 62-63 | Abolishes effect on plasma triglyceride level; when associated with N-65. | ||||
Sequence: HK → IN | ||||||
Natural variant | VAR_075670 | 63 | associated with low plasma triglyceride level; fails to suppress LPL activity in vitro; dbSNP:rs146749211 | |||
Sequence: K → T | ||||||
Mutagenesis | 63 | Abolishes inhibitory effect on LIPG/EL phospholipase activity; when associated with N-65. | ||||
Sequence: K → N | ||||||
Mutagenesis | 65 | Abolishes effect on plasma triglyceride level; when associated with 62-I-N-63. | ||||
Sequence: K → N | ||||||
Mutagenesis | 65 | Abolishes inhibitory effect on LIPG/EL phospholipase activity; when associated with N-63. | ||||
Sequence: K → N | ||||||
Natural variant | VAR_075671 | 91 | associated with low plasma triglyceride level; fails to suppress LPL activity in vitro; dbSNP:rs139334976 | |||
Sequence: E → G | ||||||
Natural variant | VAR_067283 | 127 | in dbSNP:rs72649573 | |||
Sequence: L → F | ||||||
Natural variant | VAR_075672 | 164 | associated with low plasma triglyceride level; fails to suppress LPL activity in vitro; dbSNP:rs775976787 | |||
Sequence: L → F | ||||||
Natural variant | VAR_075673 | 173 | associated with low plasma triglyceride level; fails to suppress LPL activity in vitro; no effect on protein secretion; dbSNP:rs149624466 | |||
Sequence: N → S | ||||||
Mutagenesis | 204-205 | Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with S-221; S-224 and S-235. | ||||
Sequence: RR → TT | ||||||
Mutagenesis | 221 | Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with 204-T-T-205; S-224 and S-235. | ||||
Sequence: R → ST | ||||||
Mutagenesis | 224 | Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with 204-T-T-205; S-221 and S-235. | ||||
Sequence: R → S | ||||||
Mutagenesis | 235 | Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with 204-T-T-205; S-221 and S-224. | ||||
Sequence: R → T | ||||||
Natural variant | VAR_075674 | 259 | common allele in African americans; associated with low plasma triglyceride level; fails to suppress LPL activity in vitro; no effect on protein folding; dbSNP:rs77871363 | |||
Sequence: M → T | ||||||
Natural variant | VAR_075675 | 288 | abolishes protein secretion; associated with low plasma triglyceride level; dbSNP:rs763904695 | |||
Sequence: R → Q | ||||||
Natural variant | VAR_075676 | 288 | abolishes protein secretion; associated with low plasma triglyceride level | |||
Sequence: Missing | ||||||
Natural variant | VAR_075677 | 292 | abolishes protein secretion; associated with low plasma triglyceride level; dbSNP:rs138899888 | |||
Sequence: S → P | ||||||
Natural variant | VAR_075678 | 344 | abolishes protein secretion; associated with low plasma triglyceride level; dbSNP:rs1334979946 | |||
Sequence: Y → S | ||||||
Natural variant | VAR_075679 | 375 | abolishes protein secretion; associated with low plasma triglyceride level; dbSNP:rs768802285 | |||
Sequence: E → K | ||||||
Natural variant | VAR_075680 | 417 | abolishes protein secretion; associated with low plasma triglyceride level; dbSNP:rs376210525 | |||
Sequence: Y → C | ||||||
Natural variant | VAR_049071 | 418 | in dbSNP:rs4145257 | |||
Sequence: N → Y |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 524 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, glycosylation, disulfide bond.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-16 | |||||
Sequence: MFTIKLLLFIVPLVIS | ||||||
Chain | PRO_0000435904 | 17-221 | ANGPTL3(17-221) | |||
Sequence: SRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQLRRTSIQEPTEISLSSKPR | ||||||
Chain | PRO_0000435903 | 17-224 | ANGPTL3(17-224) | |||
Sequence: SRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQLRRTSIQEPTEISLSSKPRAPR | ||||||
Chain | PRO_0000009122 | 17-460 | Angiopoietin-related protein 3 | |||
Sequence: SRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQLRRTSIQEPTEISLSSKPRAPRTTPFLQLNEIRNVKHDGIPAECTTIYNRGEHTSGMYAIRPSNSQVFHVYCDVISGSPWTLIQHRIDGSQNFNETWENYKYGFGRLDGEFWLGLEKIYSIVKQSNYVLRIELEDWKDNKHYIEYSFYLGNHETNYTLHLVAITGNVPNAIPENKDLVFSTWDHKAKGHFNCPEGYSGGWWWHDECGENNLNGKYNKPRAKSKPERRRGLSWKSQNGRLYSIKSTKMLIHPTDSESFE | ||||||
Glycosylation | 115 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 226 | O-linked (GalNAc) threonine | ||||
Sequence: T | ||||||
Disulfide bond | 246↔274 | |||||
Sequence: CTTIYNRGEHTSGMYAIRPSNSQVFHVYC | ||||||
Glycosylation | 296 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 357 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 394↔408 | |||||
Sequence: CPEGYSGGWWWHDEC |
Post-translational modification
O-glycosylated at Thr-226 by GALNT2; blocks processing and activation by proprotein convertases.
In part proteolytically cleaved by proprotein convertases; proposed to be involved in activation.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expressed principally in liver. Weakly expressed in kidney. Binds to adipocytes. Increased expression and colocalization with activated ITGB3 in glomeruli of patients with nephrotic syndrome showing effaced podocyte foot processes (at protein level).
Induction
Down-regulated by insulin.
Gene expression databases
Organism-specific databases
Structure
Family & Domains
Features
Showing features for region, coiled coil, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 17-165 | Sufficient to inhibit LPL lipase activity | ||||
Sequence: SRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLK | ||||||
Region | 17-207 | Sufficient to inhibit LIPG/EL phospholipase activity | ||||
Sequence: SRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQLRRTS | ||||||
Region | 32-56 | Required for inhibition of LPL lipase activity | ||||
Sequence: EPKSRFAMLDDVKILANGLLQLGHG | ||||||
Coiled coil | 85-210 | |||||
Sequence: LSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQLRRTSIQE | ||||||
Domain | 237-455 | Fibrinogen C-terminal | ||||
Sequence: VKHDGIPAECTTIYNRGEHTSGMYAIRPSNSQVFHVYCDVISGSPWTLIQHRIDGSQNFNETWENYKYGFGRLDGEFWLGLEKIYSIVKQSNYVLRIELEDWKDNKHYIEYSFYLGNHETNYTLHLVAITGNVPNAIPENKDLVFSTWDHKAKGHFNCPEGYSGGWWWHDECGENNLNGKYNKPRAKSKPERRRGLSWKSQNGRLYSIKSTKMLIHPTD |
Domain
The fibrinogen C-terminal domain is sufficient to mediate endothelial cell adhesion.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length460
- Mass (Da)53,637
- Last updated1999-11-01 v1
- Checksum6279465FEEB91F56
Sequence caution
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 134 | in Ref. 3; BAG37708 | ||||
Sequence: L → P |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF152562 EMBL· GenBank· DDBJ | AAD34156.1 EMBL· GenBank· DDBJ | mRNA | ||
AY358273 EMBL· GenBank· DDBJ | AAQ88640.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315304 EMBL· GenBank· DDBJ | BAG37708.1 EMBL· GenBank· DDBJ | mRNA | ||
AY569015 EMBL· GenBank· DDBJ | AAS66984.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
FJ515851 EMBL· GenBank· DDBJ | ACS13743.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471059 EMBL· GenBank· DDBJ | EAX06583.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC007059 EMBL· GenBank· DDBJ | AAH07059.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. | |
BC058287 EMBL· GenBank· DDBJ | AAH58287.1 EMBL· GenBank· DDBJ | mRNA |